Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides a compound, comprising an amide of the formula: 
wherein R1 and R2 are independently hydrogen, halo, amino, nitro, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl methyl or lower alkyl sulfinyl;
R is xe2x80x94(CH2)mxe2x80x94R3 or lower alkyl containing from 2 to 4 carbon atoms;
R3 is cycloalkyl having from 3 to 8 carbon atoms;
R4 is 
or an unsubstituted or a mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms selected from the group consisting of sulfur, or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of halo or 
m is 0 or 1;
n is 0, 1, 2, 3 or 4;
R7 is hydrogen or lower alkyl; and
xcex94 denotes a trans configuration across the double bond;
or a pharmaceutically acceptable salt thereof.
The compounds of formula I are glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes.
This invention provides a compound, comprising an amide of the formula: 
wherein R1 and R2 are independently hydrogen, halo, amino, nitro, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfinyl, lower alkyl sulfonyl, lower alkyl sulfonyl methyl or perfluoro-lower alkyl sulfonyl;
R is xe2x80x94(CH2)mxe2x80x94R3 or lower alkyl containing from 2 to 4 carbon atoms;
R3 is cycloalkyl having from 3 to 8 carbon atoms;
R4 is 
or an unsubstituted or a mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms selected from the group consisting of sulfur or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of halo or 
m is 0 or 1;
n is 0, 1, 2, 3 or 4;
R7 is hydrogen or lower alkyl;
xcex94 denotes a trans configuration across the double bond;
or a pharmaceutically acceptable salt thereof which are useful as glucokinase activators for increasing insulin secretion in the treatment of type II diabetes. In accordance with this invention, it has been found that the compounds of formula I having the trans configuration across the double bond have this glucokinase activity. On the other hand, the compounds of formula I which have a cis configuration across the double bond do not have this glucokinase activity.
When the term xe2x80x9ccisxe2x80x9d is utilized in this application, it designates that the two largest substituents attached across the double bond are on the same side of the double bond. The term xe2x80x9ctransxe2x80x9d as utilized in this application, designates that the largest substituents attached across the double bond are on opposite sides of the double bond and have the xe2x80x9cExe2x80x9d-configuration.
As used throughout this application, the term xe2x80x9clower alkylxe2x80x9d includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl, most preferably methyl. As used herein, the term xe2x80x9chalogen or haloxe2x80x9d unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine and iodine. As used herein, xe2x80x9cperfluoro-lower alkylxe2x80x9d means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc., most preferred is trifluoromethyl.
As used herein the term xe2x80x9carylxe2x80x9d signifies mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more positions with halogen, nitro, lower alkyl, or lower alkoxy substituents and polynuclear aryl groups, such as naphthyl, anthryl, and phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups. Preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl. As used herein, the term xe2x80x9clower alkoxyxe2x80x9d includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy. The term xe2x80x9carylalkylxe2x80x9d denotes an alkyl group, preferably lower alkyl, in which one of the hydrogen atoms can be replaced by an aryl group. Examples of arylalkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4-methoxybenzyl and the like.
As used herein, the term xe2x80x9clower alkanoic acidxe2x80x9d denotes lower alkanoic acids containing from 2 to 7 carbon atoms such as propionic acid, acetic acid and the like. The term xe2x80x9clower alkanoylxe2x80x9d denotes monovalent alkanoyl groups having from 2 to 7 carbon atoms such as propionoyl, acetyl and the like. The term xe2x80x9caroic acidsxe2x80x9d denotes aryl alkanoic acids where aryl is as defined above and alkanoic contains from 1 to 6 carbon atoms. The term xe2x80x9caroylxe2x80x9d denotes aroic acids wherein aryl is as defined hereinbefore, with the hydrogen group of the COOH moiety removed. Among the preferred aroyl groups is benzoyl.
During the course of the reaction the various functional groups such as the free carboxylic acid or hydroxy groups will be protected via conventional hydrolyzable ester or ether protecting groups. As used herein the term xe2x80x9chydrolyzable ester or ether protecting groupsxe2x80x9d designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective hydroxyl or carboxyl group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxcyclic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Example of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxcyclic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro, ethylchloro formate being preferred. A suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or xcex1-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
The term xe2x80x9camino protecting groupxe2x80x9d designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups utilized in peptide synthesis. Especially preferred are those amino protecting groups which are cleavable under mildly acidic conditions from about pH 2.0 to 3. Particularly preferred amino protecting groups such as t-butoxycarbonyl carbamate, benzyloxycarbonyl carbamate, 9-flurorenylmethyl carbamate. The heteroaromatic ring defined by R4 can be an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring having from 1 to 2 heteroatoms selected from the group consisting of nitrogen, or sulfur and connected by a ring carbon to the amine of the amide group shown. The heteroaromatic ring contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be sulfur, or nitrogen. Among the preferred heteroaromatic rings are pyridinyl, pyrimidinyl and thiazolyl; most preferred are pyridinyl and thiazolyl. These heteroaromatic rings which constitute R4 are connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of the heteroaromatic ring which is connected via the amide linkage to form the compound of formula I cannot contain any substituent. When R4 is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring, the preferred rings are those which contain a nitrogen heteroatom adjacent to the connecting ring carbon and a second heteroatom adjacent to the connecting ring carbon or adjacent to said first heteroatom.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
The compound of formula I of this invention constitutes two preferred species, i.e., the compound of formula 
wherein xcex94, R, R1 and R2 and R7 are as above and the compound of the formula 
wherein R, R2, R1 and xcex94 are as above; and
R11 is an unsubstituted or a mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms selected from the group consisting of sulfur or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of halo or 
n is 0, 1, 2, 3 or 4; and
R7 is hydrogen or lower alkyl.
In accordance with one embodiment of the compound of formula I-A, R can be a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclohexyl (compound I-A1). Among the various embodiments of the cyclohexyl amides of compound I-A1 are included, those compounds where one of R1 and R2 is hydrogen, halo, lower alkyl sulfonyl or perfluoro lower alkyl and the other of said R1 and R2 is halo, lower alkyl sulfonyl or perfluoro lower alkyl and particularly those compounds one of R1 and R2 is hydrogen or lower alkyl sulfonyl or perfluoro lower alkyl sulfonyl and the other is lower alkyl sulfonyl or perfluoro lower alkyl. Another embodiment of the compound of formula I-A are those compounds where R is a lower alkyl group containing from 2 to 4 carbon atoms (the compounds of formula I-A2). Among the embodiments of the compounds of formula I-A2 are those compounds where one of R1 and R2 is hydrogen, halo, lower alkyl sulfonyl or perfluoro lower alkyl and the other of said R1 and R2 is halo, lower alkyl sulfonyl or perfluoro lower alkyl.
An embodiment of the compound of formula I-B are those compounds where R11 is an unsubstituted or mono-substituted thiazole ring. When R11 is an unsubstituted thiazole ring, R can be a lower alkyl group containing from 2 to 4 carbon atoms. (compound I-B1) Among the embodiments of the compounds of the formula I-B1 are those compounds where one of R1 or R2 is hydrogen, lower alkyl sulfonyl, lower alkyl sulfonyl methyl, perfluoro lower alkyl, halo, nitro and the other of said R1 or R2 is lower alkyl sulfonyl, lower alkyl sulfonyl methyl, perfluoro lower alkyl, halo or nitro and preferably those compounds of formula IB-1 where one of R1 and R2 is hydrogen, lower alkyl sulfonyl and the other of said R1 and R2 is lower alkyl sulfonyl.
An embodiment of the compound of formula I-B are whose compounds where R is a cycloalkyl having from 3-8 carbon atoms (compound IB-2).
Among the embodiments of compounds of formula I-B2 are those compounds where the cycloalkyl group is cyclopentyl (IB-2a). The embodiment of compounds I-B2(a) are those compounds of formula IB-2(a) where R11 is an unsubstituted thiazole ring (compounds IB-2a(1)). Among the embodiments of the compound IB-2a(1) are those compounds where one of said R1 and R2 is hydrogen, lower alkyl sulfonyl, lower alkyl sulfonyl methyl, perfluoro lower alkyl, halo or nitro and the other of said R1 and R2 is lower alkyl sulfonyl, lower alkyl sulfonyl methyl, perfluoro lower alkyl, halo or nitro and particularly preferred embodiments of the compounds IB-2(a)(1) are those compounds wherein:
a) one of R1 or R2 is lower alkyl sulfonyl and the other is hydrogen, nitro, lower alkyl sulfonyl, halo or perfluoro lower alkyl;
b) one of R1 and R2 is halo, hydrogen or perfluoro lower alkyl and the other is perfluoro lower alkyl or halogen; and
c) one of R1 and R2 is lower alkyl sulfonyl methyl and the other is hydrogen, lower alkyl sulfonyl methyl or halogen.
Among the embodiments of compound of the formula IB-2a are those compounds where R11 is a mono-substituted thiazolyl ring which includes compounds where R11 is a halo substituted thiazole ring (compounds of the formula IB-2(a)(2)). Among the embodiments of the compounds of formula IB-2(a)(2) are those compounds where one of R1 and R2 is lower alkyl sulfonyl, hydrogen or halo and the other is lower alkyl sulfonyl or halo.
Another embodiment of compounds IB-2 are those compounds where R is cyclohexyl (compounds IB-2(b)). Among the embodiments of compounds IB-2(b) are those compounds where R1 is an unsubstituted thiazolyl ring (compound IB-2(b)(1). Among the preferred compounds of IB-2(b) are those compounds where one of R1 or R2 is hydrogen, lower alkyl sulfonyl, lower alkyl sulfonyl methyl, perfluoro lower alkyl, halo, nitro and the other is lower alkyl sulfonyl, lower alkyl sulfonyl methyl, perfluoro lower alkyl, halo or nitro and particularly
(a) where one of R1 or R2 is lower alkyl sulfonyl and the other is hydrogen, nitro, lower alkyl sulfonyl, halo or perfluoro lower alkyl;
(b) where one of R1 and R2 is halo, hydrogen or perfluoro lower alkyl and the other is perfluoro lower alkyl or halogen; and
(c) where one of R1 and R2 is lower alkyl sulfonyl methyl and the other is hydrogen, lower alkyl sulfonyl methyl or halogen.
Another embodiment of the compound IB-2(b) are those compounds where R11 is a mono-substituted thiazolyl ring and particularly a halo substituted ring (compound IB-2(b)(2)). Among the embodiments of compounds IB-2(b)(2) are those compounds where one or R1 and R2 is lower alkyl sulfonyl and the other is halogen, perfluoro lower alkyl or hydrogen.
Another embodiment of the compound IB-2 are those compounds where R is cycloheptyl (compound IB-2(d)) or cyclooctyl (compound IB-2(e)). An embodiment of the compounds (compound IB-2(d) and compound IB-2(e)) are those compounds where R11 is unsubstituted thiazolyl (compounds IB-2(d)(1) and IB-2(e)(1)) respectively. In this case, the compounds of IB-2(d)(1) and IB-2(e)(1) that are preferred are those compounds where one of R1 and R2 is lower alkyl, sulfonyl, hydrogen, halogen or perfluoro lower alkyl and the other is lower alkyl sulfonyl, halogen or perfluoro lower alkyl.
Another embodiment of the compound IB-2(d) and compound IB-2(e) are those compounds where R11 is a mono-substituted thiazolyl ring and the substitution is a halo group. In these cases, one of R1 and R2 can be hydrogen, lower alkyl sulfonyl, perfluoro lower alkyl or halogen and the other can be halogen, lower alkyl sulfonyl or perfluoro lower alkyl. In the compound IB-2(d) and IB-2(e), R11 is a monosubstituted thiazolyl, the substitution can be 
where n and R7 are as above.
In this case, these compounds are one of R1 and R2 in these compounds can be lower alkyl sulfonyl and the other of said R1 and R2 is lower alkyl sulfonyl or hydrogen.
Another class of compounds of formula IB are those compounds where R is xe2x80x94CH2xe2x80x94R3 and R3 is as above. Among the compounds included within this embodiment are compounds where R is a xe2x80x94CH2-cyclohexyl group (compound IB-3). Included among compounds IB-3 are compounds where R11 is a substituted or unsubstituted thiazolyl ring and particularly those compounds where R11 is an unsubstituted thiazolyl ring and where the substitution on the thiazolyl ring is: 
wherein n and R7 are as above.
In this case compounds where one of R1 and R2 is lower alkyl sulfonyl and the other is lower alkyl sulfonyl or hydrogen are preferred.
In accordance with embodiment of the compound of formula IB, R can be cyclopentyl. An embodiment of this class includes compounds where R11 is unsubstituted or mono-substituted pyridinyl ring. A preferred embodiment of this class is those compounds where one of R1 and R2 is hydrogen, lower alkyl sulfonyl or halogen and the other of said R1 and R2 is lower alkyl sulfonyl or halogen.
In accordance with this invention, the compounds of formula IA and IB can be prepared from the following compounds of the formula: 
wherein R1 and R2 are as above.
In accordance with this invention, the compounds of formula IA and IB are prepared from the compounds of formula V via the following reaction scheme: 
wherein R, R1, R2, R7 and R11 are as above;
R5 taken together with its attached oxygen atom forms a hydrolyzable acid protecting group and X is halogen.
The compound of formula V or XIX wherein one of R1 and R2 is nitro, thio, amino, halo, and the other is hydrogen are known materials. The amino substituted compounds of formula V or XIX can be converted to other substituents either before or after conversion to the compounds of formula IA or IB. In this respect, the amino groups can be diazotized to yield the corresponding diazonium compound, which in situ can be reacted with the desired lower alkyl thiol, perfluoro-lower alkyl thiol (see for example, Baleja, J. D. Synth. Comm. 1984, 14, 215; Giam, C. S.; Kikukawa, K., J. Chem. Soc, Chem. Comm. 1980, 756; Kau, D.; Krushniski, J. H.; Robertson, D. W, J. Labelled Compd Rad. 1985, 22, 1045; Oade, S.; Shinhama, K.; Kim, Y. H., Bull Chem Soc. Jpn. 1980, 53, 2023; Baker, B. R.; et al, J. Org. Chem. 1952, 17, 164) to yield corresponding compounds of formula V or XIX, where one of the substituents is lower alkyl thio, perfluoro-lower alkyl thio and the other is hydrogen. If desired, the lower alkyl thio or perfluoro-lower alkyl thio compounds can then be converted to the corresponding lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl substituted compounds of formula V or XIX by oxidation. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion. If it is desired to produce compounds of perfluoro-lower alkyl groups of compounds of formula V or XIX, the corresponding halo substituted compounds of formula V or XIX can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding perfluoro lower alkyl group (see for example, Katayama, T.; Umeno, M., Chem. Lett. 1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3, 630; Novak, J.; Salemink, C. A., Synthesis, 1983, 7, 597; Eapen, K. C.; Dua, S. S.; Tamboroski, C., J. Org. Chem. 1984, 49, 478; Chen, Q, -Y.; Duan, J. -X. J. Chem. Soc. Chem. Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.; Jone, C. W.; Landon, P.; Bisohp, D.; Blade, R. J., Tetrahedron Lett. 1989, 2133; Powell, R. L.; Heaton, C. A, U.S. Pat. No. 5,113,013) can be utilized to effect this conversion.
The compounds of formula V or XIX where both R1 and R2 substituents are amino can be obtained from the corresponding dinitro compound of formula V or XIX. Any conventional method of reducing a nitro group to an amine can be utilized to effect this conversion. The compound of formula V or XIX where both R1 and R2 are amine groups can be used to prepare the corresponding compound of formula V or XIX where both R1 and R2 are iodine or bromine via a diazotization reaction. Any conventional method of converting amino group to an iodo or bromo group (see for example, Lucas, H. J.; Kennedy, E. R. Org. Synth. Coll. Vol, II 1943, 351) can be utilized to effect this conversion. If it is desired to produce compounds of formula V or XIX, where both R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio groups, the compound of formula V or XIX where R1 and R2 are amino can be used as starting material. Any conventional method of converting aryl amino group to aryl thioalkyl group can be utilized to effect this conversion. If it is desired to produce compound of formula V or XIX where R1 and R2 are lower alkyl sulfonyl or lower perfluoro alkyl sulfonyl, the corresponding compounds of formula V or XIX where R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio can be used as starting material. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion. If it is desired to produce compounds of formula V or XIX, where both R1 and R2 are substituted with perfluoro-lower alkyl groups, the corresponding halo substituted compounds of formula V or XIX can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding perfluoro-lower alkyl group can be utilized to effect this conversion.
The compounds of formula V or XIX where one of R1 and R2 is nitro and the other is halo are known from the literature (see for 4-chloro-3-nitrophenyl acetic acid, Tadayuki, S.; Hiroki, M.; Shinji, U.; Mitsuhiro, S. Japanese patent, JP 71-99504, Chemical Abstracts 80:59716; see for 4-nitro-3-chlorophenyl acetic acid, Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J. Org. Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J. Tetrahedron Lett. 1995, 36, 1279). Thus, if it is desired to produce the compound of formula V or XIX where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is nitro and the other is chloro can be used as starting material. In this reaction, any conventional method of nucleophilic displacement of aromatic chlorine group with a lower alkyl thiol can be used (see for example, Singh, P.; Batra, M. S.; Singh, H, J. Chem. Res.-S 1985 (6), S204; Ono, M.; Nakamura, Y.; Sata, S.; Itoh, I, Chem. Lett, 1988, 1393; Wohrle, D.; Eskes, M.; Shigehara, K.; Yamada, A, Synthesis, 1993, 194; Sutter, M.; Kunz, W, U.S. Pat. No., U.S. Pat. No. 5,169,951). Once the compounds of formula V or XIX where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio are available, they can be converted to the corresponding compounds of formula V or XIX where one of R1 and R2 is nitro and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl using conventional oxidation procedures. If it is desired to produce compounds of formula V or XIX where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of reducing an aromatic nitro group to an amine can be utilized to effect this conversion. If it is desired to produce compounds of formula V or XIX where one of R1 and R2 is lower alkyl thio and the other is perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of diazotizing aromatic amino group and reacting it in situ with the desired lower alkyl thio can be utilized to effect this conversion. If it is desired to produce compounds of formula V or XIX where one of R1 and R2 is lower alkyl sulfonyl and the other is periluoro-lower alkyl sulfonyl, the corresponding compounds where one of R1 and R2 is lower alkyl thio and the other is perfluoro-lower alkyl thio, can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether group to the corresponding sulfone group can be utilized to effect this conversion. If it is desired to produce compounds of formula V or XIX where one of R1 and R2 is halo and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compounds where one of R1 and R2is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of diazotizing an aromatic amino group and conversion of it in situ to an aromatic halide can be utilized to effect this conversion. If it is desired to produce compounds of formula V or XIX where one of R1 and R2 is halo and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, the corresponding compounds where one of R1 and R2 is halo and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether to the corresponding sulfone can be utilized to effect this conversion. If one wishes to prepare the compound formula V or XIX where one of R1 and R2 is nitro and the other is amino, the compound of formula V or XIX where one of R1 and R2 is nitro and other is chloro can be used as a starting material. The chloro substituent on the phenyl ring can be converted to an iodo substituent (see for example, Bunnett, J. F.; Conner, R. M.; Org. Synth. Coll Vol V, 1973, 478; Clark, J. H.; Jones, C. W. J. Cheni. Soc. Chemn. Comrnnun. 1987, 1409), which in turn can be reacted with an azide transferring agent to form the corresponding azide (see for example, Suzuki, H.; Miyoshi, K.; Shinoda, M. Bull. Cheni. Soc. Jpn, 1980, 53, 1765). This azide can then be reduced in a conventional manner to form the amine substituent by reducing it with commonly used reducing agent for converting azides to amines (see for example, Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis, 1987, 48).
To produce a compound where R1 and/or R2 are lower alkyl sulfonyl methyl in the compound of formula I, one can start with the known compound of formula V where one or both R1 and R2 are methyl. The methyl groups in these compounds can be brominated by any conventional means for brominating the methyl groups on phenyl rings. This brominated compound is then treated with the sodium salt of a lower alkyl thiol (such as sodium thiomethoxide) to form the lower alkyl thio methyl compound. To produce the lower alkyl sulfonyl methyl substituent, any conventional method of oxidizing lower alkyl thio substituents to sulfones, such as described above, can be utilized to effect this conversion.
The substituents which form R1 and R2 can be added to the ring after forination of the compounds of formulas IA and IB. Hence, all of the reactions described to produce various sustituents of R1 and R2 in the compound of formula I can be carried out on the compounds of formulas IA and IB after their formation.
The compounds of formula IA and IB are prepared from the compound of formulae V or XIX as set forth in Schemes 1 or 2. In the first step of this reaction in Scheme 1, the compound of formula V is reacted with oxalyl chloride wherein the free hydrolyzable organic acid group of the oxalyl chloride is protected by any conventional acid protecting groups. Among the preferred acid protecting groups are hydrolyzable esters of oxalyl chloride. The protecting group is formed by R5. The reaction of the protected oxalyl chloride with the compound of formula V to produce the compound of formula VI is carried out via a Friedel-Crafts reaction. In carrying out this reaction, any of the conditions conventional in carrying out a Friedel-Crafts reaction can be utilized. In this reaction, R1 and R2 cannot be a nitro group. On the other hand, R1 and R2 can be an amino group. However, this amino group must be protected with a conventional hydrolyzable amino protecting group prior to carrying out the reaction. At some later stage in the reaction, these amino groups can be removed and the amino groups converted to nitro groups as described hereinbefore.
The compound of formula VI can be reacted with a triphenylphosphonium halide salt of formula IX via a Wittig reaction to produce the compound of formula VII. In carrying out this reaction any of the conditions conventional in carrying out a Wittig reaction can be utilized to effect these synthesis of the compound of formula VI with the compound of formula IX to produce the compound of formula VII. The compound of formula VII is formed as a mixture of cis and trans isomers about the double bond formed through the Wittig reaction. The mixture of cis and trans isomers of the compound of formula VII is directly hydrolyzed to the compound of formula VIII. In this hydrolysis reaction, the compound of formula VIII is produced as predominantly the trans isomer in this mixture. In addition, the trans isomer produced by this hydrolysis reaction is formed as a solid whereas the cis isomer is formed as an oily material. In view of this, it is very easy to separate the trans isomer by conventional methods of crystallization from this mixture to produce the compound of formula VIII as the pure trans isomer substantially free of the corresponding cis isomer. This crystallization can take place at this stage or at later stages of the reaction in the formation of the compounds of formula IA or IB. Therefore, by this procedure, the compound of formula IA and IB can be produced in pure trans form substantially free of the corresponding cis isomer.
In isolating the trans isomer, purification is best accomplished by hydrolyzing the protecting group xe2x80x94OR5 to the corresponding free acid the compound of formula VIII and recovering this free acid via crystallization in the form of the trans isomer free of the corresponding cis isomer. In producing the compound of formula IB in its trans form, it is preferred to carry out the crystallization procedure with this compound of formula VIII. On the other hand, purification by crystallization can be carried out utilizing the compounds of formula IB and IA. Since the trans isomer of these compounds are solid and the cis isomer are oily material, any conventional method of crystallization can be used to effect this purification.
In the next step of this process, the compound of formula VIII is coupled to a compound of formula:
R11xe2x80x94NH2xe2x80x83xe2x80x83XIV
wherein R11 is as above to produce the compound of formula IB. This coupling reaction can be carried out utilizing any of the conventional means by coupling an acid with a primary amino to produce an amide. On the other hand, the compound of formula VII can be directly coupled to the compound of formula XIV to produce the compound of formula IB without any intermediate hydrolysis steps.
In producing the compound of formula IA, the compound of formula VII is coupled with 
This reaction can be carried out by converting the compound of formula VII to the corresponding free acid by removing the protecting group R5 to form the carboxylic acid. The carboxylic acid of formula VIII can be converted to the corresponding amide by converting the acid to the acid chloride and thereafter reacting this acid chloride with ammonia. Conditions which are conventional for converting an acid to an acid chloride can be utilized in this procedure. This acid chloride is then reacted with an alkyl isocyanate of formula XV to form the urea adduct of formula IA. Any conventional method of reacting an alkyl isocyanate with an amide to form a urea linkage utilize the compound of formula IA.
The compound of formula IA can be formed as a mixture of cis and trans provided the compound of formula VII has not been purified. If desired, purification can take place with respect to the compound of formula IA to produce the compound of formula IA as the all-trans isomer free of the cis isomer. In the same maimer as the compound of formula IB or the compound of formula VIII can be purified, the compound of formula IA can be purified to produce this all trans isomer.
In accordance with another embodiment of this invention, the compound of formula VII can also be produced by the following reaction scheme. The reaction scheme 2 is applicable for producing compounds of formula IA or IB where one or both R1 and R2 is nitro. The coupling reaction can be easily carried out with any of the designated R1 and R2 groups, particularly those where R1 and R2 is nitro. 
wherein R5 taken together with its attached oxygen forms an acid protecting hydrolyzable carboxylic acid protecting group, R, R1, R2 and xcex94 are as above.
In scheme 2, the compound of formula XI can be generated in situ from either the corresponding organomagnesium reagent or organozinc reagent and soluble copper reagent (CuCN and 2LiCl) (see for example, Knochel, P.; Singer, R. D, Chem. Rev. 1993, 93, 2117). Then, the compound of formula XI is added to the compound of formula XVII in a 1,4-conjugate addition in a highly regio- and stereoselective manner to obtain a vinylcopper intermediate, which upon iodolysis with iodine produced the compound of formula XVIII in which the R and iodide are in syn relationship to each other. Compound of formula XVIII is thereafter reacted with activated zinc metal (see for example, Knochel, P.; Janakiram Rao. C, Tetrahedron, 1993, 49, 29) to produce a vinylzinc intermediate which then is coupled with the bromide or iodide compound of formula XIX in the presence of a source of Pd(0) to give the compound of formula VII. When this reaction is used, the aromatic substituent is added so that the trans formation across the double bond in the compound of formula VII occurs.
All of the compounds of formula I which include the compounds set forth in the Examples, activated glucokinase in vitro by the procedure of Example A. In this manner, they increase the flux of glucose metabolism which causes increased insulin secretion. Therefore, the compounds of formula I are glucokinase activators useful for increasing insulin secretion.
The following compounds exemplified were tested and found to have excellent glucokinase activator in vivo activity when administered in accordance with the assay described in Example B:
(E)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide;
(E)-3-Cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide;
(E)-3-Cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide;
(E)-2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-acrylamide;
(E)-3-Cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide;
(E)-3-Cyclohexyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-thiazol-2-yl-acrylamide;
(E)-N-(5-Bromo-thiazol-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylamide;
(E)-2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-acrylamide;
(E)-N-(5-Bromo-pyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide;
(E)-4-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid thiazol-2-ylamide;
(E)-2-[4-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoylamino]-thiazole-4-carboxylic acid methyl ester; and
(E)-4-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-but-2-enoic acid thiazol-2-ylamide.